The present invention relates to passive control of fluid flow through microfluidic conduits.
There has been a growing interest in the application of microfluidic systems to a variety of technical areas. For example, use of microfluidic systems for the acquisition of chemical and biological information presents certain advantages. In particular, when conducted in microfluidic volumes, complicated biochemical reactions and processes may be carried out using very small volumes of fluid. In addition to minimizing sample volume, microfluidic systems increase the response time of reactions and lower reagent consumption. Furthermore, when conducted in microfluidic volumes, a large number of complicated biochemical reactions and/or processes may be carried out (whether in serial, in parallel, or multiplexed) in a small area, such as in a single integrated device.
In the interest of minimizing the number of external interfaces to a microfluidic device having a number of fluidic circuits, it is often desirable to split a fluid flow from a single microfluidic channel into multiple channels. Beyond providing mere splitting utility, however, it would be further desirable to split flowing streams of fluid into precise and predictable proportions within a microfluidic device. Providing precise and predictable microfluidic flows can be particularly valuable in performing reactions such as chemical or biological synthesis, for example.
Generally, flow within a fluid conduit takes the path of least resistance to flow. Further generally, fluidic channels have a characteristic flow resistance that depends on factors including geometry and surface chemistry, and this characteristic flow resistance may not be easily controllable or reproducible from channel to channel within a device. The difficulty in controlling or reproducing the characteristic flow resistance is likely due in substantial part to the high surface-to-volume ratio in a microfluidic channel. It is believed that this high ratio significantly magnifies the effect of surface interactions between microscopic volumes of fluid and their associated microfluidic conduits. Thus, even slight variations in flow resistance between seemingly identical microfluidic channels receiving fluid from a common splitter may have a tangible impact on the proportion of fluid flowing in the respective channels.
A method of controlling fluid flow through microchannels by using stopping means has been proposed by McNeely, et al., in WIPO International Application Number PCT/US99123729 (Publication Number WO 00/22436), published Apr. 20, 2000. There, passive stopping means act as pressure barriers to stop fluid flow until enough pressure is generated to push, the fluid past the stopping means. McNeely, et al., is specifically directed to controlling developing flow (an advancing stream of fluid having a moving interface of liquid and gas), however, as opposed to established flow (where there is no moving meniscus and all surfaces are significantly wetted). Since the stopping means advantageously have negligible effect on established flow within the channels, they are ill-suited for splitting flowing streams of fluid into precise and predictable proportions.
Accordingly, there exists a need for devices and methods capable of precisely and predictably splitting established flows of fluids.
This invention relates to built-in means for controlling fluid flow in microfluidic devices. In one aspect of the invention, a method for precisely splitting an established fluidic flow through an upstream microfluidic channel among a plurality of downstream microfluidic channels includes the step of substantially and permanently elevating the flow resistance of each downstream channel relative to its characteristic resistance to established flow.
In another aspect of the invention, a microfluidic device includes an upstream channel containing a first established flow, a plurality of downstream channels in fluid communication with the upstream channel, a plurality of regions of permanently elevated resistance to established flow, each elevated flow resistance region associated with one of the plurality of downstream channels. Each elevated resistance region imparts a flow resistance that is substantially greater than the characteristic resistance to established flow of its associated downstream channel.
These and other aspects and advantages of the present invention will become apparent from the following detailed description of the preferred embodiments taken in conjunction with the figures.
Definitions
The term xe2x80x9cchannelxe2x80x9d or xe2x80x9cchamberxe2x80x9d as used herein is to be interpreted in a broad sense. Thus, it is not intended to be restricted to elongated configurations where the transverse or longitudinal dimension greatly exceeds the diameter or cross-sectional dimension. Rather, such terms are meant to comprise cavities or tunnels of any desired shape or configuration through which fluids may be directed. Such a fluid cavity may, for example, comprise a flow-through cell where fluid is to be continually passed or, alternatively, a chamber for holding a specified, discrete amount of fluid for a specified amount of time. xe2x80x9cChannelsxe2x80x9d and xe2x80x9cchambersxe2x80x9d may be filled with or may contain internal structures comprising, for example, valves, filters, or equivalent components and materials. A microfluidic channel has a smallest dimension that is at least about 1 micron but is less than about 500 microns.
The term xe2x80x9ccircuitxe2x80x9d or xe2x80x9cfluidic circuitxe2x80x9d as used herein refers to a fluidic path that may include one or more fluidic channels or other structures, such as may be formed in a microfluidic device and any associated fluidic interface.
The term xe2x80x9cflow resistancexe2x80x9d refers to a resistance to an established fluid flow (as opposed to the term xe2x80x9cstatic resistancexe2x80x9d that would apply to a developing fluid flow). Given that flow resistance may vary with pressure, one measure of flow resistance might be the local slope of a graph of pressure versus flow rate. Since the present invention involves elevation of flow resistance, however, relative measures of flow resistance are more pertinent than absolute measures. The magnitude of a characteristic flow resistance (associated with an unmodified microfluidic channel or fluid circuit) relative to an elevated flow resistance (associated with a modified microfluidic channel or fluid circuit) may be obtained by the following procedure: (1) flowing an established flow of fluid at a constant (e.g. regulated) pressure through an unmodified microfluidic circuit, capturing the exiting fluid, and calculating the flow rate (from measured volumetric output over time); (2) flowing an established flow of fluid at the same constant pressure through a modified circuit having an elevated flow resistance and calculating the flow rate (from measured volumetric output over time); and (3) comparing the original flow rate to the modified flow rate. Original flow rate divided by the modified flow rate yields a flow resistance factor. For example, if the modified flow rate is equal to only one-third of the original flow rate, then the flow resistance factor would be 3. A slightly different situation is the comparison of flow resistances between adjacent channels each positioned downstream of a common splitter. If a single upstream channel communicates an established flow of fluid to multiple downstream channels (each subject to an equal back-pressure, such as by connecting them to a common vent), then the relative magnitude of the flow resistance for each downstream channel may be inferred by the amount of fluid flowing through each downstream channel.
The term xe2x80x9ccharacteristic flow resistancexe2x80x9d refers to the resistance to established flow that is exhibited by an unmodified microfluidic channel or fluid circuit. Flow resistance may be elevated by various means, such as, for example, by adding a porous material to a channel or fluid circuit, or by significantly reducing one or more dimensions of a channel region.
The term xe2x80x9cmicrofluidicxe2x80x9d as used herein is to be understood, without any restriction thereto, to refer to structures or devices through which a fluid is capable of being passed or directed, wherein one or more of the dimensions is less than about 500 microns. The construction of microfluidic devices is described in co-pending applications, U.S. patent application Ser. Nos. 09/550,184 and 09/453,029, the entire contents of which are incorporated herein by reference. Such disclosures are also provided in two WIPO PCT patent applications, nos. PCT/US00/27366 and PCT/US00/27313, which were published on Apr. 12, 2001.
The term xe2x80x9coverlap regionxe2x80x9d refers to a fluidic passage between different, preferably adjacent, layers of a microfluidic device. Channels in non-adjacent layers may meet at an overlap region and be in fluid communication, such as across a porous layer disposed between the non-adjacent layers.
The term xe2x80x9cpermanently elevatedxe2x80x9d as used herein and applied to the elevation of flow resistance refers to a substantially non-reversible elevation. Preferably, flow resistance of a particular channel or fluidic circuit is permanently elevated during the manufacture of a microfluidic device. This is to be distinguished from a temporary elevation of flow resistance by reversible elevation means (e.g. a reversible valve) applied to a microfluidic channel.
The term xe2x80x9cstencilxe2x80x9d as used herein refers to a preferably substantially planar material from which one or more variously shaped and oriented portions are cut (or otherwise removed) through the thickness of the material layer to form microstructures. The outlines of the cut or removed portions comprise the lateral boundaries of microstructures that are formed by sandwiching one or more stencil layers between other stencils and/or substrates.
The term xe2x80x9cviaxe2x80x9d refers to a fluidic passage between non-adjacent layers of a microfluidic device. A simple via may include an aperture defined in a device layer that is sandwiched between other layers. A via is preferably aligned with one or more fluidic channels, chambers, or other vias. A via may be smaller, larger, or the same size as channels or vias defined in one or more adjacent device layers.